Colorectal cancer is one of the most common causes of cancer-death worldwide. Despite various advances in diagnosis and treatment of colorectal cancers, many patients with advanced colorectal cancer result in high mortality. To improve their prognosis, development of sensitive and specific diagnostic biomarkers for the detection of early-stage carcinomas and that of more effective and less harmful therapeutic drugs are desired. To attain this end, it is requisite to better understand the molecular mechanisms of colorectal carcinogenesis. Recent molecular studies have revealed that colorectal carcinogenesis involves an accumulation of genetic alternations that include genetic changes in tumor suppressor genes and/or oncogenes including APC, p53, beta-catenin and K-ras (Nishisho I, et al. Science 253: 665-669, 1991; Baker S J, et al., Science 244: 217-221, 1989; Morin P J, et al., Science 275: 1787-1790, 1997; Forrester K, et al., Nature 327: 298-303, 1987). In addition to these types of changes, epigenetic events such as altered methylation (Jones P A & Laird P W, Nat Genet 21: 163-167, 1999) and loss of imprinting (Cui H, et al., Nat Med 4: 1276-1280, 1998), and/or deregulated transcriptional control by genetic changes or other unknown mechanism(s) are involved in the genesis of colorectal tumors. Among the genes involved in carcinogenesis, we can expect that inhibition of gene products essential for proliferation and/or survival of cancer cells will result in their growth inhibition or cell death. Therefore, molecules that exert oncogenic activity and are specifically expressed in cancer cells represent promising targets for developing novel anti-cancer drugs.
Human TOM34 was discovered from human EST and cDNA databases, and predicted as a component of the mitochondrial protein import machinery, since the predicted protein shares sequence homology in the region of a 62-residue motif with known yeast Tom70 family of mitochondrial receptors (Nuttall S D, et al., DNA Cell Biol 16: 1067-1074, 1997). However, recent study disclosed that TOM34 is included mainly in the cytosolic fraction and partly in the mitochondrial and membrane fraction after fractionation of tissues and cells (Chewawiwat N, et al., J Biochem (Tokyo) 125: 721-727, 1999). Another study showed its subcellular localization in cytoplasm of HeLa cells by immunohistochemical staining (Chun-Song Yand Henry Y., Archives of Biochemistry and Biophysics 400: 105-110, 2002; Abhijit M, et al., Archives of Biochemistry and Biophysics 400: 97-104, 2002). Yeast two-hybrid screening system has shown that of TOM34 interacts in vitro with Valosin-containing protein (VCP), an AAA (ATPases associated with a variety of cellular activities) family member (Chun-Song Y, et al., Archives of Biochemistry and Biophysics 400: 105-110, 2002), or 90-kDa heat shock protein (hsp90) (Young J C, et al., J Biol Chem 273: 18007-18010, 1998). However, biological role of TOM34 remains unresolved.
It has been demonstrated that CD8+ cytotoxic T lymphocytes (CTLs) recognize epitope peptides derived from tumour-associated antigens (TAAs) presented on MHC Class I molecule, and lyse the tumor cells. Since the discovery of MAGE family as the first example of TAAs, many other TAAs have been discovered using immunological approaches (Boon T., Int J Cancer. 1993; 54(2):177-80., Boon T & van der Bruggen P, J Exp Med. 1996; 183(3):725-9., van der Bruggen P, et. al., Science. 1991; 254(5038):1643-7., Brichard V, et. al., J Exp Med. 1993; 178(2):489-95., Kawakami Y, et. al., J Exp Med. 1994; 180(1):347-52), and some of them have now been in the process of clinical development as targets of immunotherapy. TAAs discovered so far include MAGE (van der Bruggen P, et. al., Science. 1991; 254(5038):1643-7), gp100 (Kawakami Y, et. al., J Exp Med. 1994; 180(1):347-52), SART (Shichijo S, et. al., J Exp Med. 1998; 187(3):277-88), NY-ESO-1 (Chen Y T, et. al., Proc Natl Acad Sci USA. 1997; 94(5): 1914-8). At the same time, the gene products, which have been already shown to be over expressed somewhat specifically by the tumor cells, have been shown to be recognized as targets for cellular immune responses. These include p53 (Umano Y, et. al., Br J Cancer. 2001; 84(8):1052-7), HER2/neu (Tanaka H, et. al., Br J Cancer. 2001; 84(1):94-9), CEA (Nukaya I, et. al., Int J Cancer. 1999; 80(1):92-7) and others.
Although these are examples of the significant progress that have been made in the basic and clinical research (Rosenberg S A, et. al., Nat Med. 1998; 4(3):321-7., Mukherji B, et. al., Proc Natl Acad Sci USA. 1995; 92(17):8078-82., Hu X, et. al., Cancer Res. 1996; 56(11):2479-83), there are very limited number of candidate TAAs in general for treatment of adenocarcinomas including colon cancer. If there are TAAs which are abundantly expressed only in cancer cells but not in normal cells, they would be promising candidates for immunotherapeutic targets.